The present invention relates to mechanically stable pharmaceutical presentations for oral administration, comprising in addition to one or more active ingredients and at least one melt-processable matrix-forming excipient more than 10 and up to 40% by weight of a surface-active substance with an HLB of from 2 to 18, which is liquid at 20xc2x0 C. or has a drop point in the range from 20 to 50xc2x0 C. A process for producing such forms has also been found.
The production of pharmaceutical preparations by the melt extrusion process is known per se. Thus, the process described, for example, in EP-A 240 904 or EP-A 240 906 makes it possible, by a specific selection and defined mixtures of the excipients employed, to control specifically the properties of the formulations to be produced.
For example, it is possible to produce, by selecting suitable matrix polymers, preparations which release the active ingredient continuously over a lengthy period. On the other hand, it may be desirable, for example in the case of analgesics, for the active ingredient to dissolve rapidly and be released quickly. The melt extrusion process has proven to be suitable for producing rapid release and slow release formulations.
A basic requirement is, however, that the active ingredient is able to dissolve sufficiently in the aqueous medium in the digestive tract. Absorption of the active ingredient is possible only if it is in dissolved form, because only dissolved active ingredients can cross the intestinal wall. Active ingredients of low solubility may therefore not be absorbed sufficiently and, associated with this, have a low bioavailability.
There have been no lack of attempts to improve the bioavailability of active ingredients of low solubility (cf. R. Voigt; xe2x80x9cPharmazeutische Technologiexe2x80x9d, published by Ullstein Mosby, 7th edition, 1993, pages 80-85). In particular, the production of coevaporates or so-called solid dispersions, in which the active ingredient is in the form of a molecular dispersion in an excipient matrix, has frequently proved advantageous for increasing the bioavailability. When the drug form dissolves in the body, the active ingredient can be released in molecular form from such solid dispersions directly and without supplying energy of salvation.
However, the use of solid dispersions has a beneficial effect on the bioavailability of the active ingredient only if the active ingredient can also undergo rapid absorption. However, if the absorption process is slow, the active ingredient of low solubility recrystallizes in the aqueous medium of the intestinal lumen because a supersaturated solution of active ingredient may be produced on dissolution of the drug form. For this reason, the bioavailabilities which can be achieved even with solid dispersions are often unsatisfactory.
The absorption of the active ingredient is often insufficient also because the active ingredient is released too slowly from the tablet. Absorption of most active ingredients into the blood circulation takes place in the upper sections of the small intestine, i.e. relatively soon after passing through the stomach. Active ingredients which have not been adequately solubilized on reaching this region of the small intestine can be absorbed to only a limited extent.
It is therefore crucial for achieving optimal absorption rates, especially of active ingredients of low solubility which readily crystallize, to achieve rapid and sufficiently long-lasting solubilization in the aqueous medium of the digestive tract without recrystallization occurring.
The addition of surface-active substances is appropriate for this. The addition of surface-active substances to formulations of active ingredients of low solubility is generally known per se.
U.S. Pat. No. 5,834,472 discloses, for example, that the bioavailability of an antifungal agent can be improved by using a nonionic surface-active substance.
However, since most surface-active substances are liquid or semisolid at room temperature, the preparations produced to date are usually oily liquids or semisolids used to fill hard or soft gelatin capsules. However, in the case of soft gelatin capsules, interactions between excipients and the gelatin shell of the capsule are frequent and lead to leakage from the capsule.
The use of surface-active substances in tablet formulations is not possible without problems either because the liquid or semisolid surface-active substances impede compressibility in the conventional tableting process, especially when larger amounts of surface-active substances in the region of more than 10% by weight are needed to solubilize the active ingredient.
It is an object of the present invention to find mechanically stable solid formulations for oral use which can be used in particular for rapid and nevertheless long-lasting solubilization of active ingredients of low solubility after they have been liberated from the drug form.
We have found that this object is achieved by the pharmaceutical formulations defined at the outset, and a process for producing them.